Neuronal cell receptors that bind the neurotransmitter dopamine constitute a group of at least five structurally distinct proteins that can now be produced using recombinant DNA techniques. These techniques have been applied to construct cell lines that incorporate the dopamine receptor in their membranes, to provide regenerable and homogeneous substrates with which chemical libraries can be screened to identify potential CNS-active drugs.
Recent evidence strongly implicates the dopamine receptor classified as D4 in the etiology of schizophrenia. It has been suggested that compounds capable of interfering with the function of this receptor, which is present in schizophrenics at levels that are six times normal, would be useful in the treatment of this disease (Seeman et al, Nature, 1993, 365:441). Some dopamine receptor ligands currently sold as pharmaceuticals exhibit the desired affinity and antagonism for the D4 receptor, yet interact non-selectively with related dopamine receptors, particularly the D2 receptor type, which results in significant side effects that include altered motor function and tachycardia. It would be desirable to provide compounds that exhibit not only a high degree of affinity for the D4 receptor, but also a relatively low degree of affinity for the D2 receptor. In this specification, this desired combination of receptor binding properties is referred to as D4 selectivity.
Products currently marketed to treat indications in which the D4 receptor function is implicated include the dibenzodiazepine, clozapine, and the dibenzoxazepine, isoloxapine. Analysis of their dopamine receptor binding properties has shown that the preference for binding to the D4 receptor relative to the D2 receptor is about 10 fold, for both products. Similarly, both bind to the D4 receptor with about the same affinity (Ki value approximately 20 nM). More recently, selective D4 receptor antagonists have been identified among other classes of compounds (see, for example, Baker et al. U.S. Pat. No. 5,576,336 issued Nov. 19, 1996; Baker et al. U.S. Pat. No. 5,622,950 issued Apr. 22, 1997; and Baker et al. U.S. Pat. No. 5,432,177 issued Jul. 11,1995).
In the context of medical diagnostics, this non-selective binding at the D4 receptor prevents the generation of an accurate image of the localization and prevalence specifically of the D4 type of dopamine receptor. It would therefore be desirable to provide compounds that, in their radiolabeled state, bind at the D4 receptor with affinity and selectivity appropriate for diagnostic imaging purposes. When used in combination with such diagnostic imaging techniques as single photon emission tomography (SPECT) and positron emission tomography (PET), such radiolabeled compounds would be useful particularly to diagnose schizophrenia and other medical conditions associated with D4 receptor anomalies.